tbuckley/cabot-search huggingface dataset:
Current advances in temozolomide encapsulation for the enhancement of glioblastoma treatment
Authors: Nerea Iturrioz-Rodríguez, Nicolas Sampron, Ander Matheu
Journal: Theranostics (2023)

Glioblastoma is the most common and lethal brain tumor in adults. The incorporation of temozolomide (TMZ) into the standard treatment has increased the overall survival rate of glioblastoma patients. Since then, significant advances have been made in understanding the benefits and limitations of TMZ. Among the latter, the unspecific toxicity of TMZ, poor solubility, and hydrolyzation are intrinsic characteristics, whereas the presence of the blood-brain barrier and some tumor properties, such as molecular and cellular heterogeneity and therapy resistance, have limited the therapeutic effects of TMZ in treating glioblastoma. Several reports have revealed that different strategies for TMZ encapsulation in nanocarriers overcome those limitations and have shown that they increase TMZ stability, half-life, biodistribution, and efficacy, offering the promise for future nanomedicine therapies in handling glioblastoma. In this review, we analyze the different nanomaterials used for the encapsulation of TMZ to improve its stability, blood half-life and efficacy, paying special attention to polymer- and lipid-based nanosystems. To improve TMZ drug resistance, present in up to 50% of patients, we detail TMZ combined therapeutic with i) other chemotherapies, ii) inhibitors, iii) nucleic acids, iv) photosensitizers and other nanomaterials for photodynamic therapy, photothermal therapy, and magnetic hyperthermia, v) immunotherapy, and vi) other less explored molecules. Moreover, we describe targeting strategies, such as passive targeting, active targeting to BBB endothelial cells, glioma cells, and glioma cancer stem cells, and local delivery, where TMZ has demonstrated an improved outcome. To finish our study, we include possible future research directions that could help decrease the time needed to move from bench to bedside.
Engineered apoptotic bodies hitchhiking across the blood-brain barrier achieved a combined photothermal-chemotherapeutic effect against glioma
Authors: Yu Liu, Dehong Hu, Duyang Gao, Ping Gong, Hairong Zheng, Minjie Sun, Zonghai Sheng
Journal: Theranostics (2023)

Background: Glioma as a highly lethal tumor is difficult to treat since the blood-brain barrier (BBB) restricts drug delivery into the brain.It remains a huge need for developing strategies allowing drug passage across the BBB with high efficacy.Methods: Herein, we engineered drug-loaded apoptotic bodies (Abs) loaded with doxorubicin (Dox) and indocyanine green (ICG) to cross the BBB for the treatment of glioma.The confocal laser scanning microscopy was used to characterize the structure and evaluate the hitchhiking effect of the Abs.The in vivo BBB-crossing ability and photothermal-chemotherapeutic effect of the drug-loaded Abs were investigated in mice orthotopic glioma model.Results: Engineered Abs loaded with Dox and ICG were successfully prepared.The Abs were phagocytized by macrophages, actively penetrate the BBB in vitro and in vivo utilizing the hitchhiking effect.The whole in vivo process was visualized by near-infrared fluorescence signal with a signal-to-background ratio of 7 in a mouse model of orthotopic glioma.The engineered Abs achieved a combined photothermal-chemotherapeutic effect, leading to a median survival time of 33 days in glioma-bearing mice compared to 22 days in the control group.Conclusions: This study presents engineered drug carriers with the ability to hitchhike across the BBB, providing new opportunities for the treatment of glioma.
The international consensus classification of eosinophilic disorders and systemic mastocytosis
Authors: Sa A. Wang, Attilio Orazi, Jason Gotlib, Andreas Reiter, Alexandar Tzankov, Robert P. Hasserjian, Daniel A. Arber, Ayalew Tefferi
Journal: American Journal of Hematology (2023)

Abstract Based on new data and increased understanding of disease molecular genetics, the international consensus classification (ICC) has made several changes in the diagnosis and classification of eosinophilic disorders and systemic mastocytosis. Myeloid/lymphoid neoplasms with eosinophilia (M/LN‐eo) and gene rearrangements have been renamed as M/LN‐eo with tyrosine kinase gene fusions (M/LN‐eo‐TK). The category has been expanded to include ETV6::ABL1 and FLT3 fusions, and to accept PCM1::JAK2 and its genetic variants as formal members. The overlaps and differences between M/LN‐eo‐TK and BCR::ABL1 ‐like B‐lymphoblastic leukemia (ALL)/de novo T‐ALL sharing the same genetic lesions are addressed. Besides genetics, ICC for the first time has introduced bone marrow morphologic criteria in distinguishing idiopathic hypereosinophilia/hypereosinophilic syndrome from chronic eosinophilic leukemia, not otherwise specified. The major diagnostic criteria for systemic mastocytosis (SM) in the ICC remain largely based on morphology, but several minor modifications/refinements have been made in criteria related to diagnosis, subclassification, and assessment of disease burden (B‐ and C‐findings). This review is to focus on the ICC updates related to these disease entities, illustrated through changes related to morphology, molecular genetics, clinical features, prognosis, and treatment. Two practical algorithms are provided in navigating through the diagnosis and classification systems of hypereosinophilia and SM.
Analysis of Antibiotic Exposure and Development of Acute Graft-vs-Host Disease Following Allogeneic Hematopoietic Cell Transplantation
Authors: Armin Rashidi, Fei Gao, David N. Fredricks, Steven A. Pergam, Marco Mielcarek, Filippo Milano, Brenda M. Sandmaier, Stephanie J. Lee
Journal: JAMA Network Open (2023)

Importance Certain antibiotic exposures have been associated with increased rates of acute graft-vs-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Since antibiotic exposure can both affect and be affected by infections, analyzing time-dependent exposure in the presence of multiple potential confounders, including prior antibiotic exposures, poses specific analytical challenges, necessitating both a large sample size and unique approaches. Objective To identify antibiotics and antibiotic exposure timeframes associated with subsequent aGVHD. Design, Setting, and Participants This cohort study assessed allo-HCT at a single center from 2010 to 2021. Participants included all patients aged at least 18 years who underwent their first T-replete allo-HCT, with at least 6 months of follow-up. Data were analyzed from August 1 to December 15, 2022. Exposures Antibiotics between 7 days before and 30 days after transplant. Main Outcomes and Measures The primary outcome was grade II to IV aGVHD. The secondary outcome was grade III to IV aGVHD. Data were analyzed using 3 orthogonal methods: conventional Cox proportional hazard regression, marginal structural models, and machine learning. Results A total of 2023 patients (median [range] age, 55 [18-78] years; 1153 [57%] male) were eligible. Weeks 1 and 2 after HCT were the highest-risk intervals, with multiple antibiotic exposures associated with higher rates of subsequent aGVHD. In particular, exposure to carbapenems during weeks 1 and 2 after allo-HCT was consistently associated with increased risk of aGVHD (minimum hazard ratio [HR] among models, 2.75; 95% CI, 1.77-4.28), as was week 1 after allo-HCT exposure to combinations of penicillins with a β-lactamase inhibitor (minimum HR among models, 6.55; 95% CI, 2.35-18.20). Conclusions and Relevance In this cohort study of allo-HCT recipients, antibiotic choices and schedules in the early course of transplantation were associated with aGVHD rates. These findings should be considered in antibiotic stewardship programs.
Associations of Gestational Perfluoroalkyl Substances Exposure with Early Childhood BMI z-Scores and Risk of Overweight/Obesity: Results from the ECHO Cohorts
Authors: Yun Liu, Adaeze C. Wosu, Abby F. Fleisch, Anne L. Dunlop, Anne P. Starling, Assiamira Ferrara, Dana Dabelea, Emily Oken, Jessie P. Buckley, Leda Chatzi, Margaret R. Karagas, Megan E. Romano, Susan Schantz, Thomas G. O’Connor, Tracey J. Woodruff, Yeyi Zhu, Ghassan B. Hamra, Joseph M. Braun
Journal: Environmental Health Perspectives (2023)

Background: Gestational per- and polyfluoroalkyl substances (PFAS) exposure may be associated with adiposity and increased risk of obesity among children and adolescents. However, results from epidemiological studies evaluating these associations are inconsistent. Objectives: We estimated the associations of pregnancy PFAS concentrations with child body mass index (BMI) z-scores and risk of overweight/obesity in eight U.S. cohorts. Methods: We used data from 1,391 mother–child pairs who enrolled in eight Environmental influences on Child Health Outcomes (ECHO) cohorts (enrolled: 1999–2019). We quantified concentrations of seven PFAS in maternal plasma or serum in pregnancy. We measured child weight and height between the ages of 2 and 5 y and calculated age- and sex-specific BMI z-scores; 19.6% children had more than one BMI measurement. We estimated covariate-adjusted associations of individual PFAS and their mixture with child BMI z-scores and risk of overweight/obesity using linear mixed models, modified Poisson regression models, and Bayesian approaches for mixtures. We explored whether child sex modified these associations. Results: We observed a pattern of subtle positive associations of PFAS concentrations in pregnancy with BMI z-scores and risk of overweight/obesity. For instance, each doubling in perfluorohexane sulfonic acid concentrations was associated with higher BMI z-scores (β=0.07; 95% CI: 0.01, 0.12). Each doubling in perfluroundecanoic acid [relative risk (RR)=1.10; 95% CI: 1.04, 1.16] and N-methyl perfluorooctane sulfonamido acetic acid (RR=1.06; 95% CI: 1.00, 1.12) was associated with increased risk of overweight/obesity, with some evidence of a monotonic dose–response relation. We observed weaker and more imprecise associations of the PFAS mixture with BMI or risk of overweight/obesity. Associations did not differ by child sex. Discussion: In eight U.S.-based prospective cohorts, gestational exposure to higher levels of PFAS were associated with slightly higher childhood BMI z-score and risk of overweight or obesity. Future studies should examine associations of gestational exposure to PFAS with adiposity and related cardiometabolic consequences in older children. https://doi.org/10.1289/EHP11545
Bivalves Present the Largest and Most Diversified Repertoire of Toll-Like Receptors in the Animal Kingdom, Suggesting Broad-Spectrum Pathogen Recognition in Marine Waters
Authors: Amaro Saco, Beatriz Novoa, Samuele Greco, Marco Gerdol, Antonio Figueras
Journal: Molecular Biology and Evolution (2023)

Abstract Toll-like receptors (TLRs) are the most widespread class of membrane-bound innate immune receptors, responsible of specific pathogen recognition and production of immune effectors through the activation of intracellular signaling cascades. The repertoire of TLRs was analyzed in 85 metazoans, enriched on molluscan species, an underrepresented phylum in previous studies. Following an ancient evolutionary origin, suggested by the presence of TLR genes in Anthozoa (Cnidaria), these receptors underwent multiple independent gene family expansions, the most significant of which occurred in bivalve molluscs. Marine mussels (Mytilus spp.) had the largest TLR repertoire in the animal kingdom, with evidence of several lineage-specific expanded TLR subfamilies with different degrees of orthology conservation within bivalves. Phylogenetic analyses revealed that bivalve TLR repertoires were more diversified than their counterparts in deuterostomes or ecdysozoans. The complex evolutionary history of TLRs, characterized by lineage-specific expansions and losses, along with episodic positive selection acting on the extracellular recognition domains, suggests that functional diversification might be a leading evolutionary force. We analyzed a comprehensive transcriptomic data set from Mytilus galloprovincialis and built transcriptomic correlation clusters with the TLRs expressed in gills and in hemocytes. The implication of specific TLRs in different immune pathways was evidenced, as well as their specific modulation in response to different biotic and abiotic stimuli. We propose that, in a similar fashion to the remarkable functional specialization of vertebrate TLRs, the expansion of the TLR gene family in bivalves attends to a functional specification motivated by the biological particularities of these organisms and their living environment.
Determining the Optimal Use of Antibiotics in Hematopoietic Stem Cell Transplant Recipients
Authors: Miranda So
Journal: JAMA Network Open (2023)

Armin Rashidi, MD, PhD; Fei Gao, PhD; David N. Fredricks, MD; Steven A. Pergam, MD, MPH; Marco Mielcarek, MD; Filippo Milano, MD, PhD; Brenda M. Sandmaier, MD; Stephanie J. Lee, MD, MPH
Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury
Authors: Chenglong Ge, Wei Chen, Lina Zhang, Yuhang Ai, Yu Zou, Qianyi Peng
Journal: Theranostics (2023)

Rationale: Although sepsis-associated encephalopathy (SAE) is a common psychiatric complication in septic patients, the underlying mechanisms remain unclear. Here, we explored the role of the hippocampus (HPC) - medial prefrontal cortex (mPFC) pathway in cognitive dysfunction in lipopolysaccharide-induced brain injury. Methods: Lipopolysaccharide (LPS, 5 mg/kg, intraperitoneal) was used to induce an animal model of SAE. We first identified neural projections from the HPC to the mPFC via a retrograde tracer and virus expression. The activation viruses (pAAV-CaMKIIα-hM3Dq-mCherry) were injected to assess the effects of specific activation of mPFC excitatory neurons on cognitive tasks and anxiety-related behaviors in the presence of clozapine-N-oxide (CNO). Activation of the HPC-mPFC pathway was evaluated via immunofluorescence staining of c-Fos-positive neurons in mPFC. Western blotting was performed to determine protein levels of synapse- associated factors. Results: We successfully identified a structural HPC-mPFC connection in C57BL/6 mice. LPS-induced sepsis induces cognitive impairment and anxiety-like behaviors. Chemogenetic activation of the HPC-mPFC pathway improved LPS-induced cognitive dysfunction but not anxiety-like behavior. Inhibition of glutamate receptors abolished the effects of HPC-mPFC activation and blocked activation of the HPC-mPFC pathway. The glutamate receptor-mediated CaMKII/CREB/BDNF/TrKB signaling pathway influenced the role of the HPC-mPFC pathway in sepsis-induced cognitive dysfunction. Conclusions: HPC-mPFC pathway plays an important role in cognitive dysfunction in lipopolysaccharide-induced brain injury. Specifically, the glutamate receptor-mediated downstream signaling appears to be an important molecular mechanism linking the HPC-mPFC pathway with cognitive dysfunction in SAE.
Nanoblock-mediated selective oncolytic polypeptide therapy for triple-negative breast cancer
Authors: Cuiyu Zhong, Jie Li, Suiping Liu, Weirong Li, Qiang Zhang, Junpeng Zhao, Menghua Xiong, Yan Bao, Yandan Yao
Journal: Theranostics (2023)

Rationale: Broad-spectrum oncolytic peptides (Olps) constitute potential therapeutic options for treating heterogeneous triple-negative breast cancer (TNBC); however, their clinical application is limited owing to high toxicity.Methods: A nanoblock-mediated strategy was developed to induce selective anticancer activity of synthetic Olps.A synthetic Olp, C12-PButLG-CA, was conjugated to the hydrophobic or hydrophilic terminal of a poly(ethylene oxide)-b-poly(propylene oxide) nanoparticle or a hydrophilic poly(ethylene oxide) polymer.A nanoblocker, that can significantly reduce the toxicity of Olp, was screened out through hemolytic assay, and then Olps were conjugated to the nanoblock via a tumor acidity-cleavable bond to obtain the selective R Nolp ((mPEO-PPO-CDM)2-Olp).The tumor acidity responsive membranolytic activity, in vivo toxicity and anti-tumor efficacy of R Nolp were determined.Results: We found that the conjugation of Olps to the hydrophobic core of a nanoparticle but not the hydrophilic terminal or a hydrophilic polymer restricts their motion and drastically reduces their hemolytic activity.We then covalently conjugated Olps to such a nanoblock via a cleavable bond that can be hydrolyzed in the acidic tumor environment, yielding a selective R Nolp molecule.At physiological pH (pH 7.4), R Nolp remained stable with the Olps shielded by nanoblocks and exhibited low membranolytic activity.At the acidic tumor environment (pH 6.8), Olps could be released from the nanoparticles via the hydrolysis of the tumor acidity-cleavable bonds and exerted membranolytic activity against TNBC cells.R Nolp is well tolerated in mice and demonstrated high antitumor efficacy in orthotopic and metastatic mouse models of TNBC. Conclusion:We developed a simple nanoblock-mediated strategy to induce a selective cancer therapy of Olps for TNBC.
Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent β2 integrin activation in monocytes
Authors: Chaojun Tang, Guona Chen, Fan Wu, Yiren Cao, Fei Yang, Tao You, Chu Liu, Menglu Li, Shuhong Hu, Lijie Ren, Qiongyu Lu, Wei Deng, Ying Xu, Guixue Wang, Hanjoong Jo, Yonghong Zhang, Yi Wu, Brian A Zabel, Li Zhu
Journal: Cardiovascular Research (2023)

Abstract Aims Chemoattractants and their cognate receptors are essential for leucocyte recruitment during atherogenesis, and atherosclerotic plaques preferentially occur at predilection sites of the arterial wall with disturbed flow (d-flow). In profiling the endothelial expression of atypical chemoattractant receptors (ACKRs), we found that Ackr5 (CCRL2) was up-regulated in an endothelial subpopulation by atherosclerotic stimulation. We therefore investigated the role of CCRL2 and its ligand chemerin in atherosclerosis and the underlying mechanism. Methods and results By analysing scRNA-seq data of the left carotid artery under d-flow and scRNA-seq datasets GSE131776 of ApoE−/− mice from the Gene Expression Omnibus database, we found that CCRL2 was up-regulated in one subpopulation of endothelial cells in response to d-flow stimulation and atherosclerosis. Using CCRL2−/−ApoE−/− mice, we showed that CCRL2 deficiency protected against plaque formation primarily in the d-flow areas of the aortic arch in ApoE−/− mice fed high-fat diet. Disturbed flow induced the expression of vascular endothelial CCRL2, recruiting chemerin, which caused leucocyte adhesion to the endothelium. Surprisingly, instead of binding to monocytic CMKLR1, chemerin was found to activate β2 integrin, enhancing ERK1/2 phosphorylation and monocyte adhesion. Moreover, chemerin was found to have protein disulfide isomerase-like enzymatic activity, which was responsible for the interaction of chemerin with β2 integrin, as identified by a Di-E-GSSG assay and a proximity ligation assay. For clinical relevance, relatively high serum levels of chemerin were found in patients with acute atherothrombotic stroke compared to healthy individuals. Conclusions Our findings indicate that d-flow-induced CCRL2 promotes atherosclerotic plaque formation via a novel CCRL2-chemerin-β2 integrin axis, providing potential targets for the prevention or therapeutic intervention of atherosclerosis.
Brain Cell Biomarker for Preclinical Alzheimer Disease Identified
Authors: Emily Harris
Journal: JAMA (2023)

Astrocytes, cells that are involved in the brain’s support system, might play an important role in the progression of Alzheimer disease, according to results from 1016 participants with and without amyloid-β pathology who were all cognitively unimpaired. Participants were aged 70 years on average.
Mesenchymal stromal cells and alpha-1 antitrypsin have a strong synergy in modulating inflammation and its resolution
Authors: Li Han, Xinran Wu, Ou Wang, Xiao Luan, William H. Velander, Michael Aynardi, E. Scott Halstead, Anthony S. Bonavia, Rong Jin, Guohong Li, Yulong Li, Yong Wang, Cheng Dong, Yuguo Lei
Journal: Theranostics (2023)

Trauma, surgery, and infection can cause severe inflammation. Both dysregulated inflammation intensity and duration can lead to significant tissue injuries, organ dysfunction, mortality, and morbidity. Anti-inflammatory drugs such as steroids and immunosuppressants can dampen inflammation intensity, but they derail inflammation resolution, compromise normal immunity, and have significant adverse effects. The natural inflammation regulator mesenchymal stromal cells (MSCs) have high therapeutic potential because of their unique capabilities to mitigate inflammation intensity, enhance normal immunity, and accelerate inflammation resolution and tissue healing. Furthermore, clinical studies have shown that MSCs are safe and effective. However, they are not potent enough, alone, to completely resolve severe inflammation and injuries. One approach to boost the potency of MSCs is to combine them with synergistic agents. We hypothesized that alpha-1 antitrypsin (A1AT), a plasma protein used clinically and has an excellent safety profile, was a promising candidate for synergism.
Mechanical force drives the initial mesenchymal-epithelial interaction during skin organoid development
Authors: Mengyue Wang, Xun Zhou, Siyi Zhou, Miaomiao Wang, Jingwei Jiang, Wang Wu, Tiantian Liu, Wei Xu, Jinwei Zhang, Deming Liu, Yi Zou, Weiming Qiu, Man Zhang, Weiwei Liu, Zeming Li, Dehuan Wang, Tingting Li, Ji Li, Wanqian Liu, Li Yang, Mingxing Lei
Journal: Theranostics (2023)

Rationale: Stem cells self-organize to form organoids that generate mini-organs that resemble the physiologically-developed ones.The mechanism by which the stem cells acquire the initial potential for generating mini-organs remains elusive.Here we used skin organoids as an example to study how mechanical force drives initial epidermal-dermal interaction which potentiates skin organoids to regenerate hair follicles.Methods: Live imaging analysis, single-cell RNA-sequencing analysis, and immunofluorescence were used to analyze the contractile force of dermal cells in skin organoids.Bulk RNA-sequencing analysis, calcium probe detection, and functional perturbations were used to verify that calcium signaling pathways respond to the contractile force of dermal cells.In vitro mechanical loading experiment was used to prove that the stretching force triggers the epidermal Piezo1 expression which negatively regulates dermal cell attachment.Transplantation assay was used to test the regenerative ability of skin organoids.Results: We found that dermal cell-derived contraction force drives the movement of dermal cells surrounding the epidermal aggregates to trigger initial mesenchymal-epithelial interaction (MEI).In response to dermal cell contraction force, the arrangement of the dermal cytoskeleton was negatively regulated by the calcium signaling pathway which further influences dermal-epidermal attachment.The native contraction force generated from the dermal cell movement exerts a stretching force on the adjacent epidermal cells, activating the stretching force sensor Piezo1 in the epidermal basal cells during organoid culture.Epidermal Piezo1 in turn drives strong MEI to negatively regulate dermal cell attachment.Proper initial MEI by mechanical-chemical coupling during organoid culture is required for hair regeneration upon transplantation of the skin organoids into the back of the nude mice. Conclusion:Our study demonstrated that mechanical-chemical cascade drives the initial event of MEI during skin organoid development, which is fundamental to the organoid, developmental, and regenerative biology fields.
<i>In situ</i> formed scaffold with royal jelly-derived extracellular vesicles for wound healing
Authors: Dehong Tan, Wenxiang Zhu, Lujie Liu, Yuanwei Pan, Yangtao Xu, Qinqin Huang, Lingling Li, Lang Rao
Journal: Theranostics (2023)

Safe and effective wound healing can be a major clinical challenge. Inflammation and vascular impairment are two main causes of inadequate wound healing.